US8163917B2ExpiredUtilityA1
Azaindoles useful as inhibitors of Janus kinases
Est. expiryJan 17, 2026(expired)· nominal 20-yr term from priority
Inventors:Luc FarmerGabriel Martinez-BotellaAlbert PierceFrancesco G. SalituroJian WangMarion W. WannamakerTiansheng Wang
A61P 9/00A61P 37/06A61P 35/02A61P 9/02A61P 31/18A61P 7/00A61P 9/04A61P 43/00A61P 37/02A61P 3/10A61P 37/04A61P 37/00A61P 9/10A61P 35/00A61P 37/08A61P 25/00A61P 25/14A61P 25/28A61P 29/00A61P 25/16A61P 25/18A61P 21/00A61P 11/06A61P 21/02A61P 19/02A61P 19/00A61P 17/14A61K 31/5377A61K 45/06C07D 495/10A61K 31/506C07D 471/04C12Y 207/10002A61K 31/53A61K 31/517C07D 519/00C12N 9/12
95
PatentIndex Score
31
Cited by
45
References
58
Claims
Abstract
The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
Claims
exact text as granted — not AI-modified1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 3 is Cl or F;
X 1 is CR 4 ;
R 2 is H, F, R′, OH, OR′, COR′, COOH, COOR′, CONH 2 , CONHR′, CON(R′) 2 , or CN;
R 4 is H, F, R′, OH, OR′, COR′, COOH, COOR′, CONH 2 , CONHR′, CON(R′) 2 , or CN; or R 2 and R 4 , taken together, form a 5-7-membered aryl or heteroaryl ring optionally substituted with 1-4 occurrences of R 10 ;
R′ is a C 1-3 aliphatic optionally substituted with 1-4 occurrences of R 5 ;
each R 5 is independently selected from halogen, CF 3 , OCH 3 , OH, SH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN or unsubstituted C 1-2 aliphatic, or two R 5 groups, together with the carbon to which they are attached, form a cyclopropyl ring or C═O;
each R 10 is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SH, SCH 3 , NCH 3 , CN or unsubstituted C 1-2 aliphatic;
R 1 is
R″ is H or is a —C 1-2 aliphatic optionally substituted with 1-3 occurrences of R 11 ;
each R 11 is independently selected from halogen, OCH 3 , OH, SH, NO 2 , NH 2 , SCH 3 , NCH 3 , CN, CON(R 15 ) 2 or unsubstituted C 1-2 aliphatic, or two R 11 groups, together with the carbon to which they are attached, form a cyclopropyl ring or C═O;
R 6 is a C 1 - 4 aliphatic optionally substituted with 1-5 occurrences of R 12 ;
each R 12 is independently selected from halogen, OCH 3 , OH, NO 2 , NH 2 , SH, SCH 3 , NCH 3 , CN or unsubstituted C 1-2 aliphatic, or two R 12 groups, together with the carbon to which they are attached, form a cyclopropyl ring;
Ring A is a 4-8 membered saturated nitrogen-containing ring comprising up to two additional heteroatoms selected from N, O or S and optionally substituted with 1-4 occurrences of R 13 ;
each R 13 is independently selected from halogen, R′, NH 2 , NHR′, N(R′) 2 , SH, SR′, OH, OR′, NO 2 , CN, CF 3 , COOR′, COOH, COR′, OC(O)R′ or NHC(O)R′; or any two R 13 groups, on the same substituent or different substituents, together with the atom(s) to which each R 13 group is bound, form a 3-7 membered saturated, unsaturated, or partially saturated carbocyclic or heterocyclic ring optionally substituted with 1-3 occurrences of R 5 ;
R 8 is C 1-4 aliphatic optionally substituted with 1-5 occurrences of R 12 ;
R 9 is C 1-2 alkyl; or
R 8 and R 9 are taken together to form a 3-7 membered carbocyclic or heterocyclic saturated ring optionally substituted with 1-5 occurrences of R 12 ;
R 14 is H or unsubstituted C 1-2 alkyl;
R 15 is H or unsubstituted C 1-2 alkyl; and
R 7 is a C 2-3 aliphatic or cycloaliphatic optionally substituted with up to 6 occurrences of F.
2. The compound according to claim 1 , wherein the compound has formula I-A:
3. The compound according to claim 2 , wherein R 3 is Cl.
4. The compound according to claim 3 , wherein R 2 is H, F, R′, OH or OR′.
5. The compound according to claim 4 , wherein R 2 is H or F.
6. The compound according to claim 2 , wherein the compound is of formula I-A and R 4 is H, F, R′, OH or OR′, or R 2 and R 4 are taken together to form a 6-membered aryl ring.
7. The compound according to claim 6 , wherein R 4 is H or F.
8. The compound according to claim 7 , wherein if R 4 is F, then R 2 is H and if R 2 is F, then R 4 is H.
9. The compound according to claim 7 , wherein R 2 and R 4 are both H.
10. The compound according to claim 2 , wherein R 7 is CH 2 CH 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 F or CH 2 CH 2 CHF 2 .
11. The compound according to claim 10 , wherein R 7 is CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 CH 3 or CH 2 CH 2 CF 3 .
12. The compound according to claim 11 , wherein R 7 is CH 2 CF 3 .
13. The compound according to claim 1 , wherein R″ is H or CH 3 .
14. The compound according to claim 13 , wherein R″ is H.
15. The compound according to claim 2 , wherein R 14 is H.
16. The compound according to claim 2 , wherein R 15 is H.
17. The compound according to claim 1 , wherein the compound is of formula II:
wherein X 1A is CH or CF and R 1A is
18. The compound according to claim 17 , wherein R 7 is CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 CH 3 or CH 2 CH 2 CF 3 .
19. The compound according to claim 18 , wherein R 7 is CH 2 CF 3 .
20. The compound according to claim 17 , wherein R 1A is
and R 6 and the carbon atom to which it is attached form
21. The compound according to claim 20 , wherein R 1A is
and R 6 and the carbon atom to which it is attached form
22. The compound according to claim 21 , wherein R 1A is
and R 6 and the carbon atom to which it is attached form,
23. The compound according to claim 17 , wherein R 1A is
and Ring A is
and R 13 ′ is H or R 13 .
24. The compound according to claim 23 , wherein R 1A is
and Ring A is
25. The compound according to claim 24 , wherein R 1A is
and Ring A is
26. The compound according to claim 25 , wherein R 13 is absent.
27. The compound according to claim 25 , wherein Ring A is substituted with one occurrence of R 13 .
28. The compound according to claim 27 , wherein R 13 is OH, CH 3 , F, OR′ or NHR′.
29. The compound according to claim 28 , wherein R′ is C 1-2 alkyl or C 2-3 alkenyl.
30. The compound according to claim 28 , wherein R 13 is OH.
31. The compound according to claim 17 , wherein R 1A is
and R 8 and R 9 are taken together to form a ring selected from
wherein one or more carbon atoms in of said ring are optionally and independently replaced by N, O or S.
32. The compound according to claim 17 , wherein R 1A is
and R 8 , R 9 , and the carbon to which they are attached form
33. The compound according to claim 32 , wherein R 1A is
and R 8 , R 9 , and the carbon atom to which they are attached form
34. The compound according to claim 33 , wherein R 1A is
and R 8 , R 9 , and the carbon atom to which they are attached form
35. The compound according to claim 17 , wherein X 1A is CH or CF.
36. A compound selected from
37. A pharmaceutical composition comprising a compound according to any one of claim 1 , 17 , or 36 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
38. The composition according to claim 37 , additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
39. The compound according to claim 1 , wherein R 1 is
and
R 8 , R 9 , and the carbon atom to which they are attached form
40. The compound of claim 39 , wherein R 3 is Cl.
41. The compound of claim 39 , wherein R 3 is F.
42. The compound according to claim 39 , wherein R 1 is
and R 8 , R 9 , and the carbon atom to which they are attached form
43. The compound according to claim 39 , wherein R 2 is H or F, R 4 is H or F, and R 7 is CH 2 CH 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 F or CH 2 CH 2 CHF 2 .
44. The compound according to claim 43 , wherein R 2 is H, R 4 is H or F, and R 7 is CH 2 CH 3 , CH 2 CF 3 , CH 2 CHF 2 or CH 2 CH 2 F.
45. The compound according to claim 44 , wherein R 2 is H, R 4 is H, and R 7 is CH 2 CF 3 .
46. The compound according to claim 39 , wherein R″ is H or CH 3 and R 14 is H.
47. The compound according to claim 1 , wherein R 1 is
and R 6 and the carbon atom to which it is attached form
48. The compound according to claim 47 , wherein R 1 is
and R 6 and the carbon atom to which it is attached form
49. The compound according to claim 47 , wherein R 2 is H or F, R 4 is H or F, and R 7 is CH 2 CH 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 F or CH 2 CH 2 CHF 2 .
50. The compound according to claim 49 , wherein R 2 is H, R 4 is H or F, and R 7 is CH 2 CH 3 , CH 2 CF 3 , CH 2 CHF 2 or CH 2 CH 2 F.
51. The compound according to claim 50 , wherein R 2 is H, R 4 is H, and R 7 is CH 2 CF 3 .
52. The compound according to claim 47 , wherein R″ is H or CH 3 and R 14 is H.
53. The compound according to claim 1 , wherein R 1 is
and Ring A is
and R 13 ′ is H or R 13 .
54. The compound according to claim 53 , wherein R 1 is
and Ring A is
55. The compound according to claim 53 , wherein R 2 is H or F, R 4 is H or F, and R 7 is CH 2 CH 3 , CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CH 3 , CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 F or CH 2 CH 2 CHF 2 .
56. The compound according to claim 55 , wherein R 2 is H, R 4 is H or F, and R 7 is CH 2 CH 3 , CH 2 CF 3 , CH 2 CHF 2 or CH 2 CH 2 F.
57. The compound according to claim 56 , wherein R 2 is H, R 4 is H, and R 7 is CH 2 CF 3 .
58. The compound according to claim 53 , wherein R 14 is H or CH 3 .Cited by (0)
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